In recent years, the number of diabetic patients has increased due to westernized diets and a chronic lack of exercise, etc. In diabetic patients, chronic hyperglycemia causes reductions in both insulin secretion and insulin sensitivity, which in turn will cause elevation of blood glucose levels and lead to exacerbation of symptoms. Drugs conventionally used as therapeutic agents for diabetes include biguanides, sulfonylureas, glycosidase inhibitors and insulin-resistance improving agents. However, adverse side effects of these drugs have been reported; for example, lactic acidosis for biguanides, hypoglycemia for sulfonylureas, and diarrhea for glycosidase inhibitors. It is now strongly desired to develop therapeutic agents for diabetes that depend on a new mechanism of action which is different from those conventionally proposed.
Phloridzin, a naturally-occurring glucose derivative, is reported to produce a hypoglycemic effect by inhibiting sodium-dependent glucose cotransporter 2 (SGLT2) present at the S1 site of renal proximal tubules resulting in inhibiting excessive glucose reabsorption in the kidney and in accelerating the glucose excretion (see Nonpatent Document 1). Until now, an increasing number of studies have been conducted to develop therapeutic agents for diabetes that depend on SGLT2 inhibition.
For example, compounds used as SGLT2 inhibitors are reported in JP 2000-080041 A (Patent Document 1), International Publication No. WO01/068660 (Patent Document 2), International Publication No. WO04/007517 (Patent Document 3) and so on. However, phloridzin and the compounds disclosed in these patent applications have a problem in that, when administered orally, they are readily hydrolyzed by the action of glycosidase or the like present in the small intestine, and hence rapidly lose their pharmacological effects. Moreover, in the case of phloridzin, its aglycon phloretin is reported to strongly inhibit sugar transporters of the facilitated diffusion type. For example, there is a report showing that phloretin produces an adverse effect of reducing intracerebral glucose levels when intravenously administered to rats (see, e.g., Nonpatent Document 2).
For these reasons, attempts have been made to convert these compounds into their prodrug forms with the aim of avoiding such digestion problems and improving absorption efficiency. However, although it is desired that prodrugs when administered are precisely metabolized into active compounds in or near their target organs, stable effects are often difficult to achieve due to the action of various metabolic enzymes present in the body and large variations among individuals. Other attempts have also been made to replace glycosidic linkages in these compounds by carbon-carbon linkages (see Patent Documents 4 to 8). However, there still remains a demand for further improvements in their pharmaceutical properties, including activity and metabolic stability.    Patent Document 1: Japanese Patent Publication 2000-080041 A    Patent Document 2: International Publication No. WO01/068660 Pamphlet    Patent Document 3: International Publication No. WO04/007517 Pamphlet    Patent Document 4: US Patent Publication 2001/041674 A    Patent Document 5: US Patent Publication 2002/137903 A    Patent Document 6: International Publication No. WO01/027128 Pamphlet    Patent Document 7: International Publication No. WO02/083066 Pamphlet    Patent Document 8: International Publication No. WO04/013118 Pamphlet    Non-patent Document 1: J. Clin. Invest., 93, 397 (1994)    Non-patent Document 2: Stroke, 14, 388 (1983)